Dual functions of Runx proteins for reactivating CD8 and silencing CD4 at the commitment process into CD8 thymocytes

To understand how CD8 expression is regulated during the transition process from CD4+8+ (CD4 and CD8 double positive, DP) to CD4-8+ (CD8 single positive, CD8SP) cells in the thymus, the involvement of Runx proteins in the alteration of chromatin configuration was investigated. Using the chromatin immunoprecipitation assay, we first demonstrated that Runx proteins bind to the stage-specific CD8 enhancer, as well as the CD4 silencer, in CD8SP thymocytes. Among Runx family members, Runx3 expression was initiated in DP thymocytes receiving a positive selection signal and increased in concert with differentiation to the CD8SP stage. Furthermore, reactivation of the CD8 gene, as well as CD4 silencing, was suppressed in positively selected thymocytes of Runx dominant-negative transgenic mice. These results suggest that Runx proteins, especially Runx3, are involved in lineage specification of CD8 T cells and provide important information for understanding the mechanism for the mutually exclusive expression of coreceptors in mature thymocytes.     

Dietary nucleic acid and intestinal microbiota synergistically promote a shift in the Th1/Th2 balance toward Th1-skewed immunity

BACKGROUND: Intestinal microbiota are known to play an important role in the establishment of oral tolerance, thereby protecting the organism from food allergies. Dietary intake of nucleic acid (NA) is also reported to have such an anti-allergic effect; however, one unsolved question is whether or not dietary NA would act through a process of toll-like receptor 9 signaling activated by DNA containing a CpG motif, a well-known sequence leading to immunostimulatory activity. In this study, we focused on the question of whether the addition of dietary NA lacking CpG motifs would allow continued modulation of the Th1/Th2 balance. METHODS: Germ free (GF) and Bifidobacterium-infantis-monoassociated BALB/c mice were maintained on either an NA-free casein diet or on an NA-supplemented casein diet for 4 weeks. Thereafter, both the in vivo anti-casein antibody levels and in vitro splenocyte cytokine secretion pattern were evaluated. RESULTS: Feeding with a casein diet elicited a substantial increase in the serum anti-casein-specific IgG1, IgG2a, and IgE levels of GF mice fed the NA free-diet. The in vitro cytokine production profile showed that enhanced IL-4 production in the GF mice fed the NA free-diet was markedly reduced by the supplementation with dietary NA in both the GF and B.-infantis-monoassociated mice. In addition, IFN-gamma secretion increased in the B.-infantis-reconstituted mice fed the diet containing NA. CONCLUSIONS: These results suggest that dietary intake of NA devoid of CpG motifs may prevent the development of allergies via acceleration of Th1-dominant immunity.     

Nodal marginal zone B cell lymphoma with prominent follicular colonization with deletion of chromosome 13

Nodal marginal zone B cell lymphoma is a rare type of malignant lymphoma and appears to be heterogeneous. Here we report a 60-year-old woman with stage I splenic type of nodal marginal zone B cell lymphoma with prominent follicular colonization. She was treated only by radiation therapy, and remained free of disease on examination for 4 years. The lymph node cells showed an abnormal chromosome of deletion 13, although neither bone marrow cells nor peripheral blood cells demonstrated the same abnormal chromosome. This type of chromosomal abnormality has not been previously reported and may be related to good prognosis in the present case.     

Reduced hydration status characterized by disproportionate elevation of blood urea nitrogen to serum creatinine among the patients with cerebral infarction

The significance of fluid metabolism among the patients with cerebral infarction has barely mentioned in the literature despite the several reports suggesting the potential risk of reduced hydration status for the development of cerebral infarction. The aim of the this study is to explore the validity of the presumable relationship between hydration status and cerebral infarction. Ninety-seven patients with cerebral infarction from April 1, 2008 to March 31, 2009 were retrospectively investigated, and their hydration status were evaluated by using several clinical parameters such as a blood urea nitrogen to serum creatinine (BUN/Cr) ratio of >25 and plasma osmolality. Subjects with active infection, congestive heart failure, hepatic failure, gastrointestinal bleeding, or a malignancy were excluded since these conditions should modulate the absolute value of BUN/Cr ratio without a change in hydration status. Twenty-eight patients (29%) were considered as having reduced hydration status. The BUN/Cr ratio decreased significantly after the initiation of medical support (median 21.3; IR: 18.1-24.6), including oral or parenteral fluid supplementation, in comparison to the values at the time of patient admission (median 30.0; IR: 26.8-40.7; p < 0.0001). Similar decreases were also observed in the hematocrit, hemoglobin, and plasma osmolality. The group considered to have reduced hydration status had a significantly higher prevalence of cardioembolic stroke than the other subjects. The hydration status may be a contributing factor to subtypes of cerebral infarction. Whether our findings are also the case with overall patients with cerebral infarction should be evaluated in greater detail.     

IL-15 exacerbates collagen-induced arthritis with an enhanced CD4+ T cell response to produce IL-17

IL-15 is thought to be involved in the pathogenesis of rheumatoid arthritis (RA). We found that IL-15 plays an important role in the development of murine collagen-induced arthritis (CIA). The incidence and severity of CIA were slightly decreased in IL-15 KO mice but were increased in IL-15 Tg mice compared with wild-type (WT) mice. The levels of type II collagen (CII)-specific IL-17 production were significantly increased in IL-15 Tg mice compared with WT mice with CIA. Expression of IL-23R was up-regulated in CD4(+) T cells in IL-15 Tg mice but down-regulated in IL-15 KO mice compared with WT mice. In correlation with the expression levels of IL-23R, IL-17 production by CD4(+) T cells in response to exogenous IL-23 was increased in IL-15 Tg mice compared with WT mice. Furthermore, exogenous IL-15 synergized with IL-23 to induce CII-specific IL-17 production by CD4(+) T cells in vitro. Taken together, these results indicate that IL-15 plays an important role in the progression of CIA through increasing antigen-specific IL-17 production by CD4(+) T cells.     

Renal damage in obstructive nephropathy is decreased in Skp2-deficient mice

Ubiquitin-dependent degradation of the cyclin-dependent kinase inhibitor p27 mediated by SCF-Skp2 ubiquitin ligase is involved in cell cycle regulation. Proliferation of tubular cells is a characteristic feature in obstructed kidneys of unilateral ureteral obstruction. Comparing Skp2(+/+) mice with Skp2(-/-) mice, we investigated the involvement of Skp2, a component of SCF-Skp2 ubiquitin ligase for p27, in the progression of renal lesions in unilateral ureteral obstructed kidneys. mRNA expression of Skp2 was markedly increased in the obstructed kidneys from Skp2(+/+) mice and peaked 3 days after unilateral ureteral obstruction. Renal atrophy, tubular dilatation, tubulointerstitial fibrosis, and increases in alpha-smooth muscle actin expression, the number of tubular cells, and proliferating tubular cells positive for Ki67 were observed in the obstructed kidneys from Skp2(+/+) mice; however, these findings were significantly attenuated in Skp2(-/-) mice. The p27 protein level was increased in the obstructed kidneys but was significantly greater in Skp2(-/-) mice. The number of Ki67-positive p27-negative cells was lower in obstructed kidneys from Skp2(-/-) mice than Skp2(+/+) mice, whereas that of Ki67-negative p27-positive cells was greater in Skp2(-/-) mice. These findings suggest that p27 accumulation, which results from SCF-Skp2 ubiquitin ligase deficiency in Skp2(-/-) mice, is involved in the amelioration of renal damage induced by obstructive nephropathy.     

A role of Helicobacter pylori infection in the development of duodenal ulcer after adult living-related liver transplantation

Gastrointestinal bleeding caused by peptic ulcer disease is one of the serious complications of living-related liver transplantation (LRLT). The aim of this study was to clarify the factors involved in peptic ulcer formation in adult LRLT recipients. Forty consecutive adult LRLT recipients without a history of peptic ulcer disease were studied. Twenty-five patients (62.5%) tested positive for Helicobacter pylori. After LRLT, duodenal ulcer (DU) developed in six patients, and all of them tested positive for H. pylori. In contrast, none of the H. pylori-negative patients developed DU. Preoperative serum gastrin levels in patients with DU were significantly higher than in those without DU, irrespective of H. pylori infection. Preoperative pepsinogen I levels in patients with DU were significantly higher than in those without DU with H. pylori infection. These data suggest involvement of H. pylori infection in the development of DU after LRLT. Eradication of H. pylori may prevent the development of DU after LRLT particularly in patients with hypergastrinemia and high serum pepsinogen I.